Pathways downstream of Shc and Grb2 are required for cell transformation by the tpr-Met oncoprotein.
The Tpr-Met oncoprotein, which is a member of a family of tyrosine kinase oncoproteins generated following genomic rearrangement, consists of the catalytic kinase domain of the hepatocyte growth factor/scatter factor receptor tyrosine kinase (Met) fused downstream from sequences encoded by the tpr gene. We have previously demonstrated that a single ... tyrosine residue in the carboxyl terminus, Tyr489, is highly phosphorylated and is essential for efficient transformation of Fr3T3 fibroblasts by Tpr-Met and for the association of Tpr-Met with the Grb2 adaptor protein and phosphatidylinositol 3'-kinase. We show here that Tyr489 is also required for association of Tpr-Met with phospholipase Cgamma and the tyrosine phosphatase, SHPTP2/Syp. To distinguish which of these substrates are required for cell transformation by the Tpr-Met oncoprotein, we generated a novel Tpr-Met mutant that selectively fails to associate with the Grb2 adaptor protein. Utilizing this mutant, together with additional Tpr-Met mutants containing Tyr to Phe substitutions, we have demonstrated that transformation of Fr3T3 fibroblasts by the Tpr-Met oncoprotein is dependent upon pathways downstream of Shc and Grb2 and that pathways downstream of phosphatidylinositol 3'-kinase, phospholipase Cgamma, and SHPTP2/Syp are insufficient for transformation.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, 3T3 Cells, Adaptor Proteins, Signal Transducing, Animals, Base Sequence, Cell Line, Cell Transformation, Neoplastic, DNA Primers, Enzyme Activation, GRB2 Adaptor Protein, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Oncogene Proteins, Fusion, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Proteins, Type C Phospholipases
1-Phosphatidylinositol 3-Kinase, 3T3 Cells, Adaptor Proteins, Signal Transducing, Animals, Base Sequence, Cell Line, Cell Transformation, Neoplastic, DNA Primers, Enzyme Activation, GRB2 Adaptor Protein, Intracellular Signaling Peptides and Proteins, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Oncogene Proteins, Fusion, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Proteins, Type C Phospholipases
J. Biol. Chem.
Date: May. 31, 1996
PubMed ID: 8662733
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